Project Summary Polymicrobial communities that exhibit synergistic pathogenicity cause periodontal disease, one of the most common infections of humans. As a model system for the study of polymicrobial synergy, we are investigating the interactions of Treponema denticola and Porphyromonas gingivalis. Heterotypic communities develop as physiologically compatible organisms modulate their own and their partner?s physiology resulting in enhanced fitness and virulence. Synergistic metabolism can reduce the nutrient requirements of the entire community, thereby increasing the pathogenic potential. T. denticola and P. ginigvalis display metabolic cross-feeding to enhance the growth of both bacteria. Additional bacterial members of the subgingival plaque community are known to cooperate in metabolic exchanges. However, the molecular details of metabolic cross-feeding and how it functions to drive pathogenicity are understudied. The overall premise of this study is to characterize the metabolic interactions between T. denticola and P. gingivalis to better understand the pathogenic potential of the community. Aim 1 will evaluate how glycine is acquired and utilized as a carbon and energy source. Aim 2 will characterize the response of T. denticola to mutualistic metabolism by enhancing biofilm development and invasion into gingival epithelial cells. Aim 3 will demonstrate that metabolic cross-feeding enhances the pathogenicity of T. denticola. Our overall long-term goal is to translate these novel molecular mechanisms into the development of future therapeutic approaches targeting polymicrobial pathogenic communities. The candidate, Dr. Miller, has a longstanding interest in the microbiology of periodontal diseases. After completing the mentored (K99) phase, his goal is to become an assistant professor at a leading research university, where he plans to continue his research on interbacterial interactions that promote periodontal diseases. This K99/R00 proposal is designed to complement Dr. Miller?s previous research expertise and provide him with the opportunity to develop the necessary skills and experiences to become an independent research scientist. Dr. Miller will receive additional training under the guidance of the primary mentor, Dr. Richard Lamont, and co-mentor, Dr. David Scott. Both mentors were carefully selected for as they each contribute diverse, yet complementary expertise for the successful completion of this research program. Additionally, Dr. Miller has assembled a committee of scientists with various backgrounds who will provide oversight and advise his scientific and career development during his transition to independence.